Pregnancy poses a unique immunological paradox. For pregnancy to succeed, the fetus, which expresses paternal alloantigens, needs to avoid rejection by maternal immune cells. In addition, the immune system of the mother, while tolerant to the fetus, has to be functional for combating infections. Several mechanisms exist at the maternal-fetal interface and systemically, which regulate the immune status of the pregnant mother. These include secreted products by the trophoblast cells of the placenta, such as pregnancy specific glycoproteins (PSGs). Our proposal centers on the mechanisms by which PSGs exert an immune regulatory role during pregnancy. We found that different form of recombinant PSG1 generated in our laboratory is bound to the anti-inflammatory cytokine transforming growth factor 1 (TGF-b1). This observation was extended to native PSG1, purified from serum of pregnant women. Whether PSG1 is just a carrier of TGF-b1 or it can modify its action remains to be determined. We hypothesize that binding of PSG1 to latent TGF-b1 results in the activation of this important cytokine, which besides its anti-inflammatory function, regulates many important processes during pregnancy including trophoblast invasion, endothelial cell function, and extracellular matrix deposition. A better understanding of the relationship between PSGs and TGF-b is necessary before PSGs can be used as a therapeutic agent. Lower than normal circulating levels of PSGs are found in pregnant serum of women with different pregnancy pathologies such as small for gestational age fetuses. Recently, we described that besides its immune regulatory function, PSG1 is pro-angiogenic. PSG1 binds to the heparin and chondroitin sulfate in syndecans and this interaction results in the formation of capillary-like structures by endothelial cells. The domains, and amino acids within a domain, which interact with syndecans or TGF-b have not been identified and this information is required for a design of a PSG-based therapy intervention with the desired effect. The activation of TGF-b is the rate limiting step in the function of this pluripotent cytokine. While the importance of TGF-b is very well recognize during pregnancy, its activation is very poorly understood in most tissues, including the maternal-fetal interface. This project will define the mechanism of action o PSG1 and address a possible novel mechanism of TGF-b1 and TGF-b2 activation. PUBLIC HEALTH RELEVANCE: Aberrant placental angiogenesis and excessive inflammation at the maternal-fetal interface can lead to adverse pregnancy outcomes including spontaneous abortion, preterm labor, preeclampsia, and intrauterine growth restriction. This project studies the mechanism of action at the molecular level of a family of placental proteins known as pregnancy specific glycoproteins, which play a role in the process of placental vascular development and regulation of the immune response. Insights gained from these studies will help to generate novel therapeutic strategies for conditions with excessive immune activation unrelated to pregnancy and for certain pregnancy complications.